Implantable osmotic pump

ABSTRACT

A pump, includes a pump engine; a compartment adapted to store a fluid, the compartment being disposed at least partially around the pump engine, and a piston disposed within the compartment, the compartment and the engine being configured to cause the piston to travel within the compartment along an arcuate path and to force a volume of the fluid out of the pump.

[0001] This application is a continuation under 35 USC §120 of copendingand commonly assigned U.S. patent application Ser. No. 09/838,662 filedon Apr. 19, 2001.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates generally to the field of drugdelivery systems. In particular, the present invention relates toimplantable osmotic pump systems.

[0004] 2. Description of the Related Art

[0005] Since the beginning of modern medicine, drugs have beenadministered orally. Patients have taken pills as recommended by theirphysician. The pills must pass through the digestive system and then theliver before they reach their intended delivery site (e.g., the vascularsystem). The actions of the digestive tract and the liver typicallyreduce the efficacy of medication by about 33%. Furthermore, oralmedications must be administered by the patient. Patient compliance tothe prescribed delivery profile is often poor. Studies suggest that 40%of patients do not comply with their oral medication consumptioninstructions. This causes two concerns. First, patients who do not taketheir medication as instructed are not maintaining blood drug levelswithin the therapeutic window and are therefore not receiving adequatetherapy for their disease. A second, worse scenario than receiving toolittle medication occurs when the patient may be taking too muchmedication either by accident or purposefully in order to make up for amissed dose. Both of these patient-controlled scenarios can be dangerousto the patient, and at a minimum may prolong or aggravate their disease.Subcutaneous drug delivery and intravenous drug delivery have theadvantage of bypassing the acidic and enzymatic action of the digestivesystem. Unfortunately, IV administration requires the use of apercutaneous catheter or needle to deliver the drug to the vein. Thepercutaneous site requires extra cleanliness and maintenance to minimizethe risk of infection. Infection is such a significant risk that IVadministration is often limited to a number of weeks, at most. Inaddition, the patient must wear an external pump connected to thepercutaneous catheter if the therapy is intended to last longer than afew hours and the patient desires to be ambulatory. Subcutaneous drugdelivery can be either partially implanted or totally implanted.Partially implanted systems rely on a percutaneous catheter or needlestick to deliver the medication, therefore, partially implanted systemshave the same limitations as IV systems. Totally implanted systems havefewer maintenance requirements and are far less prone to infection thanIV or partially implanted systems.

[0006] In the 1970s, a new approach toward sustained drug delivery wascommercialized for animal use only. The driving force of such pumps wasbased upon a new approach utilizing the principle of osmosis. A recentexample of such a pump is described listed in U.S. Pat. No. 5,728,396.This patent discloses an implantable osmotic pump that achieves asustained delivery of leuprolide. The pump includes a right-cylindricalimpermeable reservoir that is divided into a water-swellable agentchamber and a drug chamber, the two chambers being divided by a movablepiston. Fluid from the body is imbibed through a semipermeable membraneinto the water-swellable agent chamber. As the water-swellable agent inthe water-swellable agent chamber expands in volume, it pushes on themovable piston, which correspondingly decreases the volume of the drugchamber and causes the drug to be released through a diffusion outlet ata substantially constant rate.

[0007] A limitation of the osmotic pump disclosed in theabove-identified patent, however, is that its infusion rate cannot beadjusted once it is implanted. This is acceptable for medications thatdo not need rate adjustment, but often physicians desire to adjust theinfusion rate based on the clinical status of the patient. One exampleof when a physician would want to increase the infusion rate is in thefield of pain management. Osmotic pumps can be used to delivermedication to treat pain lasting over an extended period of time. Pain,however, often increases with time, and sometimes patients becometolerant to pain medications; therefore, more medication is needed toeffectively treat the pain. The system disclosed in the above-identifiedpatent does not allow a rate increase after implantation, so thephysician must surgically remove the current implant and implant anadditional pump to deliver the correct dosage. However, the prospect ofyet another surgical procedure may cause many patients to forego thepotential benefits of the larger dose and may also cause theirphysicians to advise against the initial procedure altogether.

[0008] The aspect ratio of such cylindrical osmotic pump deliverydevices is large, and often not compatible with the human body. Indeed,the human body does not have naturally-formed right-cylindrical cavitiesin which to implant such devices in the patient, in an unobtrusive andcomfortable manner.

[0009] What are needed, therefore, are improved osmotic pumps. What arealso needed are improved implantable osmotic pumps that conform to thepatient's anatomy and that more closely match the topology of theimplant site. Also needed are novel implantable osmotic pumps for longterm delivery of a pharmaceutical agent that do not rely upon aright-cylindrical pharmaceutical agent compartment and/or conventionalcylindrical pistons. Also needed are implantable pumps that enable thephysician to increase the dose of pharmaceutical agent delivered to thepatient without, however, removing the pump from the implant site.

SUMMARY OF THE INVENTION

[0010] It is an object of the present invention, therefore, to provideimproved pumps. Another object of the present invention is to provideimproved implantable osmotic pumps that conform to the patient's anatomyand that more closely match the topology of the implant site. A stillfurther object is to provide novel implantable osmotic pumps for longterm delivery of a pharmaceutical agent that do not rely upon aright-cylindrical pharmaceutical agent compartment and/or conventionalcylindrical pistons. Preferably, such improved pumps should enable thephysician to increase the dose of pharmaceutical agent delivered to thepatient without removing the pump from the implant site.

[0011] In accordance with the above-described objects and those thatwill be mentioned and will become apparent below, an implantable osmoticpump for delivering a pharmaceutical agent to a patient, includes acatheter; an osmotic engine; a pharmaceutical agent compartment; avolume of pharmaceutical agent that includes Sufentanil within thepharmaceutical agent compartment, and a piston disposed within thecompartment, the compartment being configured such that the osmoticengine causes the piston to travel within the compartment along anarcuate path and deliver the pharmaceutical agent through the catheterwhen the pump is implanted in the patient, wherein the pump isconfigured for: a daily delivery rate of Sufentanil of up to about 125micrograms per day when the catheter is placed intraventricularly; adaily delivery rate of Sufentanil of up to about 250 micrograms per daywhen the catheter is placed intrathecally; a daily delivery rate ofSufentanil of up to about 750 micrograms per day when the catheter isplaced epidurally; a daily delivery rate of Sufentanil of up to about1500 micrograms per day when the catheter is placed subcutaneously, anda daily delivery rate of Sufentanil of up to about 1500 micrograms perday when the catheter is placed intravascularly.

[0012] The compartment may be disposed at least partially around theosmotic engine. The osmotic engine may include a base, a cylindricalwall attached to the base and a free end opposite the base.

[0013] The pump may further include a housing configured to enclose atleast the osmotic engine and the compartment. The housing may include afirst housing half and a second housing half that mates with the firsthousing half. Each of the first and second housing halves may define asaucer shape. Each of the first and the second housing halves may besubstantially circular in shape. The first housing half may define asubstantially circular opening. The pump may further include a membraneenclosure, the membrane enclosure being partially surrounded by theosmotic engine and may include an initial dose semipermeable membranethat may be configured to allow water from the patient to reach theosmotic engine when the pump is implanted. The pump may be configured todeliver an initial dose of the pharmaceutical agent to the patient at aselected initial infusion rate, the selected initial infusion rate beingrelated to a thickness, a composition and/or a surface area of theinitial dose semipermeable membrane. The initial dose semipermeablemembrane may be fitted with an initial dose impermeable membrane thatinitially seals the initial dose semipermeable membrane. The pump mayfurther include a volume of a saturated saline solution between theinitial dose semipermeable membrane and the initial dose semipermeablemembrane. The pump may further include a dose escalation assembly fittedin the membrane enclosure, the dose escalation assembly being adapted toselectively increase an amount of water from the patient that reachesthe osmotic engine when the pump is implanted. The dose escalationassembly may include a first impermeable membrane configured to enablewater from the patient to reach the osmotic engine through a first fluidpath only after being breached. The dose escalation assembly mayinclude: a first impermeable membrane configured to enable water fromthe patient to reach the osmotic engine through a first fluid path onlyafter being breached, and a second impermeable membrane configured toenable water from the patient to reach the osmotic engine through asecond fluid path only after being breached, the first path beingdistinct from the second path. The first and second impermeablemembranes may be disposed in the membrane enclosure in a stackedconfiguration in which the first impermeable membrane must be breachedbefore the second impermeable membrane can be breached. The first fluidpath may include a first semipermeable membrane and the second fluidpath may include a second semipermeable membrane that is distinct fromthe first semipermeable membrane. The pump may be configured to delivera first dose of the pharmaceutical agent to the patient at a selectedfirst infusion rate and a second dose of the pharmaceutical agent to thepatient at a selected second infusion rate that may be greater than thefirst infusion rate, the selected first and second infusion rates beingrelated to a thickness, a composition and/or a surface area of the firstand second semipermeable membranes, respectively. The osmotic engine mayinclude a hygroscopic salt, for example. The osmotic engine may includean absorbent polymer. The absorbent polymer may include a materialselected from a group including poly(acrylic acid), potassium salt;poly(acrylic acid), sodium salt; poly(acrylic acid-co-acrylamide),potassium salt; poly(acrylic acid), sodium salt-graft-poly(ethyleneoxide); poly (2-hydroxethyl methacrylate); poly(2-hydroxypropylmethacrylate) and poly(isobutylene-co-maleic acid) or derivativesthereof.

[0014] The compartment may have a substantially constant inner diameterover a length thereof. The compartment may have a non-constant innerdiameter over a length thereof. The catheter may include a radiopaquetip. The piston may include one of a sphere, an elastomeric cylinder andan elastomeric conical section. The piston may include at least one ofstainless steel, a refractory metal, plastic, nylon and rubber. Thesufentanil may be at a concentration up to about 500,000 μg/mL, forexample. The dose escalation assembly may include: a first saturatedsaline solution between the first impermeable membrane and the firstsemipermeable membrane, and a second saturated saline solution betweenthe second impermeable membrane and the second semipermeable membrane.

[0015] The present invention, according to another embodiment thereof,is a method of delivering a pharmaceutical agent to a patient,comprising steps of: implanting a pump into the patient, the pumpincluding a pump engine and a compartment adapted to store apharmaceutical agent, and causing a piston to travel a distance withinthe compartment along an arcuate path and to deliver a dose ofpharmaceutical agent out of the compartment.

[0016] The implanting step may be carried such that the pharmaceuticalagent is delivered one of intravascularly, subcutaneously, epidurally,intrathecally and intraventricularly. The pharmaceutical agent mayinclude Sufentanil and the pump may be configured for: a daily deliveryrate of Sufentanil of up to about 125 micrograms per day when theimplanting step is carried out such that the pharmaceutical agent isdelivered intraventricularly; a daily delivery rate of Sufentanil of upto about 250 micrograms per day when the implanting step is carried outsuch that the pharmaceutical agent is delivered intrathecally; a dailydelivery rate of Sufentanil of up to about 750 micrograms per day whenthe implanting step is carried out such that the pharmaceutical agent isdelivered epidurally; a daily delivery rate of Sufentanil of up to about1500 micrograms per day when the implanting step is carried out suchthat the pharmaceutical agent is delivered subcutaneously, and a dailydelivery rate of Sufentanil of up to about 1500 micrograms per day whenthe implanting step is carried out such that the pharmaceutical agent isdelivered intravascularly. Travel of the piston within the compartmentmay cause a delivery of a volume up to about 20 μL/day over a treatmentperiod, for example. The method may further comprise the step ofselectively increasing the dose in a stepwise manner over a treatmentperiod without removing the pump from the patient. The pump engine mayinclude an osmotic engine and the pump may include an initial dosesemipermeable membrane initially exposed to the patient and at least onesecond semipermeable membrane initially not exposed to the patient andthe increasing step may include a step of selectively exposing the atleast one second semipermeable membrane to the patient. The pump theengine may include an osmotic engine in fluid communication with thepiston and the causing step may include a step of increasing a volume ofthe osmotic engine.

[0017] The present invention, according to yet another embodimentthereof, is a pump, comprising: a pump engine; a compartment adapted tostore a fluid, the compartment being disposed at least partially aroundthe pump engine, and a piston disposed within the compartment, thecompartment and the engine being configured to cause the piston totravel within the compartment along an arcuate path and to force avolume of the fluid out of the pump.

[0018] The pump engine may include an osmotic engine. The fluid mayinclude a pharmaceutical agent. A catheter may be coupled to thecompartment. The pump may be configured to be fully implantable in abody and pump engine and the compartment may be enclosed in abiocompatible pump housing. The pump may include a dose escalationassembly, the escalation assembly being configured to selectivelyincrease the dose of fluid delivered. The dose escalation assembly mayinclude means for increasing the dose delivered in a stepwise manner.The piston may include one of a sphere, an elastomeric cylinder and anelastomeric conical section.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] For a further understanding of the objects and advantages of thepresent invention, reference should be made to the following detaileddescription, taken in conjunction with the accompanying figures, inwhich:

[0020]FIG. 1 is a perspective view of the osmotic pump according to anembodiment of the present invention.

[0021]FIG. 2 is an exploded view of the osmotic pump according to anembodiment of the present invention, showing the major componentsthereof.

[0022]FIG. 3 is a plan view of the osmotic pump according to anembodiment of the present invention in which the first half of thehousing has been removed.

[0023]FIG. 4 is a cross sectional view of the osmotic pump of FIG. 3,taken along lines BB′.

[0024]FIG. 5 is a cross sectional view of the osmotic pump of FIG. 3,taken along lines AA′.

[0025]FIG. 6 is a plan view of the second half of the osmotic pumphousing, according to an embodiment of the present invention.

[0026]FIG. 7 is a cross sectional view of the second half of the osmoticpump housing, taken along lines CC′.

[0027]FIG. 8 is a perspective view of the first half of the osmotic pumphousing according to an embodiment of the present invention.

[0028]FIG. 9 is a plan view of the first half of the osmotic pumphousing of FIG. 8.

[0029]FIG. 10 is a cross-sectional view of the first half of the osmoticpump housing of FIG. 9, taken along lines DD′.

[0030]FIG. 11 is a plan view of an embodiment of the membrane enclosure,according to an embodiment thereof.

[0031]FIG. 12 is a perspective view of the membrane enclosure of FIG.11, showing the semipermeable membrane wells in dashed lines.

[0032]FIG. 13 is a plan view of an impermeable membrane can of anosmotic pump according to an embodiment of the present invention,showing the internal surface and through bore thereof in dashed lines.

[0033]FIG. 14 shows a side view of the impermeable membrane can of FIG.13.

[0034]FIG. 15 is a plan view of the osmotic engine of the osmotic pump,according to an embodiment of the present invention.

[0035]FIG. 16 is a side view of the osmotic engine of FIG. 15.

[0036]FIG. 17 is a plan view of the coiled tube, according to anembodiment of the present invention.

[0037]FIG. 18 is a cross-sectional view of the tube of FIG. 17, takenalong line EE′.

[0038]FIG. 19 is a cross-sectional view of the coiled tube of FIG. 17,taken along line FF′.

[0039]FIG. 20 illustrates the tube coupled to a catheter, according toan embodiment of the present invention.

[0040]FIG. 21 illustrates the distal tip of the catheter of FIG. 20,according to an embodiment of the present invention.

[0041]FIG. 22 illustrates the proximal end of the catheter of FIG. 20,according to an embodiment of the present invention.

[0042]FIG. 23 shows an embodiment of a piston within the coiledpharmaceutical agent compartment, according to an embodiment of thepresent invention.

[0043]FIG. 24 shows a further embodiment of a piston within the coiledpharmaceutical agent compartment, according to an embodiment of thepresent invention.

[0044]FIG. 25 shows a further embodiment of still another piston withinthe coiled pharmaceutical agent compartment, according to an embodimentof the present invention.

[0045]FIG. 26 shows a first step of a method by which the impermeablemembrane of the first impermeable membrane may be breached so as toescalate a dose of pharmaceutical agent delivered to the patient,according to an embodiment of the present invention.

[0046]FIG. 27 shows a second step of a method by which the impermeablemembrane of the first impermeable membrane may be breached so as toescalate a dose of pharmaceutical agent delivered to the patient,according to an embodiment of the present invention.

[0047]FIG. 28 shows a third step of a method by which the impermeablemembrane of the first impermeable membrane can may be breached so as toescalate a dose of pharmaceutical agent delivered to the patient,according to an embodiment of the present invention.

[0048]FIG. 29 shows a fourth step of a method by which the impermeablemembrane of the second impermeable membrane can may be breached so as tofurther escalate a dose of pharmaceutical agent delivered to thepatient, according to an embodiment of the present invention.

[0049]FIG. 30 shows a fifth step of a method by which the impermeablemembrane of the second impermeable membrane can may be breached so as tofurther escalate a dose of pharmaceutical agent delivered to thepatient, according to an embodiment of the present invention.

[0050]FIG. 31 shows a sixth step of a method by which the impermeablemembrane of the second impermeable membrane can may be breached so as tofurther escalate a dose of pharmaceutical agent delivered to thepatient, according to an embodiment of the present invention.

[0051]FIG. 32 is a plan view of another embodiment of the membraneenclosure, according to the present invention, showing the OFF featureof the present invention.

[0052]FIG. 33 is a perspective view of the membrane enclosure of FIG.32, showing the semipermeable membrane wells in dashed lines and the OFFswitch feature of the present invention.

[0053]FIG. 34 is an exploded view of another embodiment of an osmoticpump according to the present invention.

[0054]FIG. 35 is an exploded view of a three-stage osmotic pump,according to another embodiment of the present invention.

[0055]FIG. 36a is a top view of a three stage osmotic pump according tothe present invention, showing the internal structure thereof in dashedlines.

[0056]FIG. 36b is a reduced-size (relative to FIG. 36a) top view of athree stage osmotic pump, showing selected exemplary dimensions thereof.

[0057]FIG. 37 is a cross-sectional view of a three stage osmotic pumpaccording to the present invention, taken along cross-sectional line BB′of FIG. 36.

[0058]FIG. 38 is a cross-sectional view of a three stage osmotic pumpaccording to the present invention, taken along cross-sectional line AA′of FIG. 36.

[0059]FIG. 39 is a cross-sectional view of the filter assembly 312 ofFIG. 35.

[0060]FIG. 40 is a front view of the filter assembly 312 of FIG. 35.

[0061]FIG. 41 is a cross-sectional view of a piston, according to anembodiment of the present invention.

[0062]FIG. 42 is a perspective view of a single stage osmotic pumpaccording to another embodiment of the present invention.

[0063]FIG. 43 is an exploded view of a single stage osmotic pumpaccording to the present invention.

[0064]FIG. 44 is a top view of a single stage osmotic pump according tothe present invention, showing internal components thereof in dashedlines.

DESCRIPTION OF THE INVENTION

[0065]FIG. 1 is a perspective view and FIG. 2 shows an exploded view ofthe pump 100 according to an embodiment of the present invention.Considering FIGS. 1 and 2 collectively, the pump 100 includes a pumpengine 108 and a substantially toroidal compartment around the engine108. The toroidal compartment is bounded by an inner radius 207 and anouter radius 208 and is adapted to contain a fluid, such as apharmaceutical agent. According to an embodiment of the presentinvention, the pharmaceutical agent compartment is tube-shaped and isdefined by an inner lumen 110 of a tube 109 that may be coiled at leastpartially around the osmotic engine 108. The tube 109 has a proximal end184 and a distal end 186. The tube 109 may include or be formed of, forexample, polyimid. A piston 162 is disposed in the tube-shapedcompartment 110. The piston is adapted to travel (in the direction fromthe proximal end 184 to the distal end 186 of the tube 109) within thetube-shaped compartment 110 and to cause a volume of fluid to be forcedout of the distal end 186 of the tube 109. As shown in FIG. 1, acatheter 102 may be coupled to the distal end 186 of the tube 109, toenable the fluid forced out the distal end 186 of the tube 109 to bedelivered to the intended delivery site within the patient. In oneembodiment of the present invention, the pump engine 108 includes anosmotic engine. The pump 100 may further include a pump housing 101 thatis configured to enclose (at least) the pump engine 108 and the tube109. As shown in FIG. 2, the pump housing 101 may include a firsthousing half 106 and a mating second housing half 104. According to anembodiment of the present invention, the first and second pump housinghalves 106, 104 mate to one another like a clamshell, in a fluid-tightfashion. As shown, the first and second housing halves 106, 104 may eachhave a generally circular outline (as may the entire pump 100) and havea generally define a saucer shape. The first housing half 106 mayfurther define an opening 140, which may be circular in shape.

[0066] The present invention will now be described in terms of animplantable osmotic pump for delivering a pharmaceutical agent to apatient, although the present invention is not so limited. The pumpand/or the catheter 102 may be implanted intravascularly,subcutaneously, epidurally, intrathecally and/or intraventricularly, forexample. As shown in FIG. 2 as well as in FIGS. 15 and 16, the pumpengine 108 (referred to hereafter as osmotic engine 108, although thepresent invention is not limited to osmotic-type pump engines) may beshaped like hollow, open-ended right cylinder. The osmotic engine 108 ishygroscopic and may include a salt block or a “salt wafer” and/or mayinclude an absorbent polymer, such as poly(acrylic acid), potassiumsalt; poly(acrylic acid), sodium salt; poly(acrylic acid-co-acrylamide),potassium salt; poly(acrylic acid), sodium salt-graft-poly(ethyleneoxide); poly (2-hydroxethyl methacrylate) and/or poly(2-hydroxypropylmethacrylate) and poly(isobutylene-co-maleic acid). Suitable absorbentpolymers are available from Aldrich, Inc. of Milwaukee, Wis., forexample. The osmotic engine 108 may include a base that may be disposedin a correspondingly shaped depression defined in the second housinghalf 104 and a cylindrical wall attached to the base.

[0067] According to an embodiment of the present invention, the pump 100may include a generally cylindrical-shaped membrane enclosure 112. Themembrane enclosure 112 may be fitted within and partially surrounded bythe pump engine 108. The membrane enclosure 112 is dimensioned toclosely fit the opening 140 defined in the first housing half 106. Themembrane enclosure 112 may include an initial dose semipermeablemembrane (formed of or including cellulose acetate, for example), asshown in FIG. 5, to create a fluid path for water through the initialwater access port 130 defined in the membrane enclosure 112 to theosmotic engine 108. The initial water access port 130 may be spanned bya thin impermeable membrane 182, thereby defining an interstitial spacebetween the initial dose semipermeable membrane and the impermeablemembrane. This interstitial space may be filled with a saturated salinesolution, to keep the initial dose semipermeable membrane fully hydratedprior to implantation of the pump 100 in a patient (not shown). Prior toimplantation, the physician may breach the impermeable membrane 182spanning the initial water access port 130 to allow water from thepatient to enter the initial dose semipermeable membrane well 150 (seeFIG. 12) and migrate across the initial dose semipermeable membrane 134(see FIG. 5) to reach the osmotic engine 108. In this manner, theinitial water access port 130, the thin impermeable membrane 182 and thesaturated saline solution effectively form a pump ON switch. Indeed,after implantation of the pump but before breaching the thin impermeablemembrane 182, the pump 100 does not deliver any pharmaceutical agent tothe patient. It is only after breaching the thin impermeable membrane182 that the pump becomes effective to initiate delivery of thecontained pharmaceutical agent to the patient. The saturated salinesolution between the impermeable membrane 182 and the underlying initialdose semipermeable membrane 150 insures that the onset of delivery ofthe pharmaceutical agent is not delayed by the time required for theinitial dose semipermeable membrane 150 to hydrate.

[0068] The membrane enclosure 112 may also define a primary water accessport 132 that may be (but need not be) concentric with the circumferenceof the membrane enclosure 112. A dose escalation assembly may fit withinthe primary water access port 132. The dose escalation assembly,according to the present invention, is adapted to selectively increasethe amount of water from implantation site within the patient thatreaches the osmotic engine 108. The dose escalation assembly may includeone or more impermeable membrane cans fitted within the primary wateraccess port 132 of the membrane enclosure 112. In the embodiment of FIG.2, the dose escalation includes a first impermeable membrane can 114stacked upon a second impermeable membrane can 116 whose structure andfunction is described hereunder.

[0069] Reference is now made to FIGS. 3-5, in which FIG. 3 is a planview of the osmotic pump according to an embodiment of the presentinvention in which the first half of the housing has been removed, FIG.4 is a cross sectional view of the osmotic pump of FIG. 3, taken alonglines BB′ of FIG. 3 and FIG. 5 is a cross sectional view of the osmoticpump of FIG. 3, taken along lines AA′. FIG. 3 shows the tube 109 coiledaround the osmotic engine 108 from the proximal end 184 to the distalend thereof, shown at 186. The distal end 186 of the coiled tube 109 maybe fitted with a catheter ID tube 118 that facilitates the coupling ofthe catheter 102 to the distal end 186 of the tube 109. As shown in FIG.5, the initial water access port 130 may lead to an initial dosesemipermeable membrane 134 within the membrane enclosure 112. Themembrane enclosure 112 is configured to enable water from the patient toflow into the initial water access port 130, to migrate across theinitial dose semipermeable membrane 134 to reach the osmotic engine 108.As the water reaches the osmotic engine 108, the engine 108 swells involume and increases the osmotic pressure differential across theinitial dose semipermeable membrane 134 and pushes the piston 160 withinthe tube-shaped compartment defined by the tube 109 toward the distalend 186 thereof, as the expansion of the osmotic engine 108 isconstrained to within the tube-shaped compartment 110. In so doing, thepiston 160 displaces a volume of pharmaceutical agent within thetube-shaped compartment 110, which displaced volume of pharmaceuticalagent is delivered out of the distal end 186 of the tube 109. Thepharmaceutical agent is delivered at a selected initial infusion ratethat is related to the thickness, composition and surface area of theinitial dose semipermeable membrane 134. In the case wherein the initialdose semipermeable membrane 134 is implanted in a fully hydrated state,the pharmaceutical agent within the tube-shaped compartment is quicklydelivered to the patient at the selected initial infusion rate. If theinitial dose semipermeable membrane 134 is not pre-hydrated, thedelivery of the pharmaceutical agent may be delayed until the membrane134 becomes at least partially hydrated from water from the patientimplant site. Until at least the first impermeable membrane cans 114 isbreached, the only water that reaches the osmotic engine 108 enters thepump 100 through the initial water access port 130 to cross the initialdose semipermeable membrane 134.

[0070] As shown in FIG. 4, the membrane assembly 112 includes a firstsemipermeable membrane 120 and a second semipermeable membrane 124. Thediameter of the semipermeable membranes 120, 124 is directlyproportional to the flow rate of the pump of the present invention. Asshown, the first semipermeable membrane 120 may be (but need not be)vertically offset from the second semipermeable membrane 124 in themembrane enclosure 112. Reference is now made to FIGS. 13 and 14, ofwhich FIG. 13 is a plan view of an impermeable membrane can 114, 116 andof which FIG. 14 is a side view of the impermeable membrane can 114, 116of FIG. 13. As shown therein, the cans 114, 116 include a cylindricalsidewall 154 and a through bore defined therein. Specifically, thesidewall of the first impermeable membrane can 114 defines a firstthrough bore 122 and the sidewall of the second impermeable membrane can116 defines a second through bore 126. An impermeable membrane 152(shown in FIGS. 13 and 14 in its intact state) spans one of the freeends of each of the cans 114, 116. The impermeable membranes 152,according to the present invention, are impermeable at least to waterfrom the patient implant site and are configured to be easily breachedby the physician, as is detailed below. The impermeable membranes 152may include or be formed of most any water impermeable material that isbiologically inert, such as titanium and/or stainless steel, coatedplatinum or platinum-iridium for radiopacity, for example. Theimpermeable membranes 152 of the first and second cans 114, 116 may besurface ground to a thickness of about 1 or 2 thousandths of an inch,for example. The impermeable membranes 152 may alternatively includepolyethylene, PET, PETG or PETE, for example. Preferably, theimpermeable membranes 152 are radiopaque, so as to be visible underfluoroscopy, once the pump 100 is implanted. For example, a layer ofradiopaque material may be sputtered or otherwise deposited on theimpermeable membranes 152, to render them visible under fluoroscopy.Preferably, the impermeable membranes 110 are adapted to be breached bythe physician or clinician, using a dose escalation pen (or a lancet orstylet as shown in FIGS. 26-31), or some other functionally similardevice. The impermeable membranes 152 of the first and secondimpermeable membrane cans 114, 116 initially seal the first and secondsemipermeable membranes 120, 124 to prevent any water originating fromthe patient's implant site from crossing the semipermeable membranes120, 124 until the impermeable membrane(s) 152 is breached, as shown at176 in FIGS. 28-31.

[0071] Returning now to FIGS. 3-5, the first and second impermeablemembrane cans 114, 116 are stacked within the membrane enclosure 112such that the respective through bores 122, 126 thereof are aligned withthe first and second semipermeable membranes 120, 122, respectively.Specifically, the first through bore 122 defined in the firstimpermeable membrane can 114 is aligned with the first semipermeablemembrane 120 and the second through bore 126 defined in the secondimpermeable membrane can 116 is aligned with the second semipermeablemembrane 124. Moreover, the impermeable membrane 152 of the firstimpermeable membrane can 114 is disposed adjacent the primary wateraccess port 132, whereas the second impermeable can 116 is disposedunder the first impermeable membrane can 114 and oriented such that theimpermeable membrane thereof is immediately adjacent the firstimpermeable membrane can 114. Although the present figures show the pump100 of the present invention equipped with two impermeable membrane cans114, 116, the present invention is not limited thereto, as a single or agreater number of impermeable membrane cans may be used along with acorresponding number of semipermeable membranes.

[0072]FIG. 6 is a plan view of the second half 104 of the osmotic pumphousing 101, according to an embodiment of the present invention andFIG. 7 is a cross sectional view thereof, taken along lines CC′. Asshown therein, the second half 104 of the pump housing 101 may have agenerally saucer-like shape. Indeed, the second half 104 of the housing101 may have a generally circular outline and may define a bulge 136therein to accommodate a portion of the osmotic engine 108 therein. Therim of the second half 104 (See FIG. 10) of the pump housing 101 alsodefines an indentation 138 adapted to mate with a corresponding featuredefined by the rim of the first half 106 of the pump housing 101. FIG. 8is a perspective view of the first half 106 of the osmotic pump housing101 according to an embodiment of the present invention, whereas FIG. 9is a plan view and FIG. 10 is a cross-sectional view thereof, takenalong lines DD′. As shown in the perspective view of FIG. 10, an opening140 is defined in the also generally saucer-shaped first half 106 of theosmotic pump housing 101. The opening 140 may be centered in the housinghalf 106 and concentric with the generally circular outline thereof, asshown in FIG. 9. The opening 140 is preferably dimensioned so as toclosely fit the membrane enclosure 112. As shown in FIG. 10, the firsthalf 106 of the pump housing 101 may define a bulge 144 that increasesthe interior volume of the pump 100 when the first and second housinghalves 106, 104 are mated to one another.

[0073]FIG. 11 is a plan view of an embodiment of the membrane housing112, according to an embodiment thereof, whereas FIG. 12 is aperspective view of the membrane housing of FIG. 11, showing thesemipermeable membrane wells in dashed lines. Considering now FIGS. 11and 12 collectively, the membrane enclosure 112 may be shaped as acylinder dimensioned to fit within the osmotic engine 108 and theopening 140 in the first housing half 106. The primary water access port132 may be a bore partially through the membrane enclosure 112. However,to best control the flow of water form the patient implant site to theosmotic engine 108, the bore defined within the membrane enclosure 112should not run the entire length of the membrane enclosure 112. Indeed,the only water paths from the implant site to the osmotic engine shouldbe through the initial dose semipermeable membrane well 150, through thefirst semipermeable membrane well 146 and/or through the secondsemipermeable membrane well 150. In contrast, the combination of theinitial water access port 130 and the initial dose semipermeable well150 runs the entire length of the membrane enclosure 112, as also shownin FIG. 5. Indeed, once the pump 100 is implanted in the patient and anyimpermeable membrane that may span the initial water access port 130 isbreached, a water path to the osmotic engine 108 may be defined straightthrough the membrane enclosure 112, as the water from the implant sitemigrates across the initial dose semipermeable membrane (shown at 134 inFIG. 5) fitted within the initial dose semipermeable membrane well 150.

[0074] First and second semipermeable membranes 120, 124 (shown in FIG.4) are fitted within the first and second semipermeable membrane wells146, 148, respectively. According to the present invention, when theimpermeable membrane 152 of the first impermeable membrane can 114 isbreached (as shown at 176 in FIGS. 28, 29 and 31), water from theimplant site may enter the primary access port 132 and travel throughthe first through bore 122 of the first impermeable membrane can 114.From there, the water may travel through a first passageway 188, definedbetween primary water access port 132 and first semipermeable membranewell 146. After crossing the first semipermeable membrane 120 disposedin the well 146, the water reaches the osmotic engine 108. This firstwater path is shown at 178 in FIGS. 28, 29 and 31. As the water reachesthe osmotic engine 108, the engine 108 swells in volume due to theosmotic pressure differential across the first semipermeable membrane120 and pushes the piston 160, 162 within the tube-shaped compartment110 defined within the tube 109 toward the distal end 186 thereof. In sodoing, the piston 160, 162 displaces a volume of pharmaceutical agentwithin the tube-shaped compartment 110, which displaced volume ofpharmaceutical agent is delivered out of the distal end 186 of the tube109. The pharmaceutical agent is delivered at a selected first infusionrate that is related to the thickness, composition and surface area ofthe first semipermeable membrane 120 and that of the initial dosesemipermeable membrane 134.

[0075] Similarly, when the impermeable membrane 152 of the secondimpermeable membrane can 116 is breached (as shown at 177 in FIGS. 28,29 and 31), water from the implant site may enter the primary accessport 132 and travel through the second through bore 126 of the secondimpermeable membrane can 116. From there, the water may travel through asecond passageway 190, defined within the enclosure 112 between theprimary water access port 132 and the second semipermeable membrane well148. After crossing the second semipermeable membrane 124 disposed inthe well 148, the water reaches the osmotic engine 108. This water pathis shown at 180 in FIG. 31. As the water reaches the osmotic engine 108,the engine 108 swells in volume due to the osmotic pressure differentialacross the second semipermeable membrane 124 and pushes the piston 160,162 within the tube-shaped compartment 110 defined by the tube 109toward the distal end 186 thereof. In so doing, the piston 160 displacesa volume of pharmaceutical agent within the tube-shaped compartment 110,which displaced volume of pharmaceutical agent is delivered out of thedistal end 186 of the tube 109. The pharmaceutical agent is delivered ata selected second infusion rate that is related to the thickness,composition and surface area of the second semipermeable membrane 124,the thickness, composition and surface area of the first semipermeablemembrane 120 and the thickness, composition and surface area of theinitial dose semipermeable membrane 134. Indeed, the infusion rate ofthe pump 100 is related to which of the semipermeable membranes 134, 120and/or 124 are currently exposed to the patient. If only the initialdose semipermeable membrane 134 is exposed to the patient, the infusionrate may be related only to the characteristics of the initial dosesemipermeable membrane 134. If both the initial dose semipermeablemembrane 134 and the first semipermeable membrane 120 are exposed to thepatient, the pump infusion rate may be related to the characteristics ofboth the initial dose and first semipermeable membranes 134, 120. Inother words, the total infusion rate of the pump 100 of the presentinvention in the state wherein both the initial dose semipermeablemembrane 134 and the first semipermeable membrane 120 are breached, maybe approximated as the sum of the individual infusion rates contributedby each of the semipermeable membranes 134 and 120. If the initial dosesemipermeable membrane 134, the first semipermeable membrane 120 and thesecond semipermeable membrane 124 are exposed to the patient, the pumpinfusion rate may be related to the characteristics of the initial dose,the first and the second semipermeable membranes 134, 120 and 124. Inother words, the total infusion rate of the pump of the presentinvention in the state wherein the impermeable membranes 134, 120 and124 are breached, may be approximated as the sum of the individualinfusion rates contributed by each of the semipermeable membranes 134,120 and 124.

[0076]FIG. 17 is a plan view of the coiled tube 109, according to anembodiment of the present invention, FIG. 18 is a cross-sectional viewof the tube 109 of FIG. 17, taken along line EE′ and FIG. 19 is across-sectional view thereof, taken along line FF′. According to thepresent invention, the piston 160 may initially (upon implantation) bedisposed within the tube-shaped compartment 110 near the proximal end184 of the tube 109. As the osmotic engine expands in volume, the onlyavailable volume for such expansion is within the tube-shapedcompartment 110. Therefore, the expansion of the osmotic engine 108forces the piston 160 to travel through the coiled tube 109 in thedirection of arrow 166, which causes a volume of pharmaceutical agent tobe delivered to the patient out of the distal end 186 of the tube 109. Acatheter ID (inner diameter) tube 118 may be fitted onto the distal end186 of the tube 109, which facilitates coupling the catheter 102thereto. As shown, the tube 109 may be coiled a number of times aroundthe membrane enclosure 112. In the embodiment shown in FIGS. 17-19, thetube 109 is coiled four times around the membrane enclosure 112 (notshown in FIGS. 17-19), although a lesser or greater number of coils mayreadily be implemented.

[0077]FIG. 20 illustrates the tube 109 coupled to a catheter 102,according to an embodiment of the present invention. FIG. 21 illustratesthe distal tip of the catheter of FIG. 20, according to an embodiment ofthe present invention and FIG. 22 illustrates the manner in which thecatheter may couple to the catheter ID tube 118. In FIG. 20, the outlineof the pump housing 101 is shown for reference purposes. The catheter102 is used to deliver the pharmaceutical agent from the catheter IDtube 118 to the target area within the patient's body. The catheter 102may be visible under fluoroscopy over its length, thereby enabling thephysician to trim the catheter to the desired length. Alternatively, thecatheter 102 may include distal radiopaque markers, for example. Asshown in FIG. 21, the distal tip 158 of the catheter 102 may included arounded, atraumatic tip. A plurality of pharmaceutical agent openings158 may be defined through the catheter wall, from the internal lumenthereof to the patient. As shown in FIG. 22, the catheter ID may befitted over the catheter ID tube 118 using a friction fit and/orsuitable biocompatible adhesive(s), for example. Any suitable radioopaque material may be used to render all or a portion or selectedportions of the catheter 102 radio opaque. For example, the catheter 102may be formed of silicone or polyurethane and may be doped with bariumsulfate, for example. The length of the catheter 102 may be most anytherapeutically effective length. A longer length, however, increasesthe dead space therein and delays the effusion of the pharmaceuticalagent into the patient, as it will take longer for the agent to travelthe length thereof. For example, the catheter 102 may be about 5 cm toabout 100 cm in length. More preferably, the catheter 102 may be about10 cm to about 30 cm in length. More preferably still, the catheter 012may be about 15 cm to about 25 cm in length. For example, the catheter102 may be about 20 cm in length. The internal diameter (ID) of theinfusion lumen of the catheter 102 may be selected within the range ofabout 0.001 inches to about 0.010 inches. The walls of the catheter 102may be about 0.001 inches to about 0.006 inches in thickness. Accordingto an embodiment of the present invention, the outer diameter (OD) ofthe catheter 102 may be selected between about 0.024 inches and about0.066 inches in thickness, for example.

[0078]FIGS. 23-25 are cross sections of the tube 109, showing variousdesigns for the piston within the tube shaped compartment 110.Considering now FIGS. 23-25 collectively, the piston of the osmotic pump100 of the present invention may be spherical, as shown at 160,cylindrical as shown at 162 or may approximate a conical section asshown at 163, although other shapes are possible. A spherical shapeminimizes the contact points of the piston 160 with the tube-shapedcompartment 110, thereby enabling the piston 160 to travel through thecompartment 110, even as the radius of curvature thereof changes formthe proximal end 184 to the distal end of the tube 109. Reference 170represents slurry from the osmotic engine 108. Indeed, reference 170 maybe considered to be an extension of the osmotic engine 108, as it swellswith water from the patient implant site through the semipermeablemembranes 134, 120 and/or 124. As the osmotic engine 108 swells involume, it exerts a force 168 on the piston 160, 162 or 163, forcing itto travel within the tube-shaped compartment 110 in the direction ofarrow 166. In so doing, the piston 160, 162, 163 displaces acorresponding volume of pharmaceutical agent 164. The piston 160, 162,163 may include stainless steel, nylon or an elastomer, for example.When the piston has a cylindrical shape, as shown on FIG. 24 at 162, thepiston 162 may be formed of an elastomeric substance, such as butylrubber, for example. Such a cylindrical piston 162 may then deform tomatch the radius of curvature of the tube-shaped compartment 110. Theinner diameter of the tube 109 (that is, the diameter of the tube-shapedcompartment 110) may be constant over the length of the tube 109 or maybecome larger or smaller over its length. In the latter case, the piston163 may assume a truncated conical shape, in which a proximal endthereof is smaller than a distal end thereof (or vice-versa), to matchthe change in inner diameter of the tube-shaped compartment 110. Toprevent the tube 109 from compressing, binding and/or kinking as theosmotic engine 108 swells, the coiled tube 109 may be encased in a hardsubstance, such as epoxy, for example.

[0079]FIG. 26-28 shows steps of a method by which the impermeablemembrane 152 of the first impermeable membrane can 114 may be breachedso as to escalate a dose of pharmaceutical agent delivered to thepatient, according to an embodiment of the present invention. FIG. 29-31shows further steps of the method by which the impermeable membrane 152of the second impermeable membrane can 116 may be breached so as tofurther escalate the dose of pharmaceutical agent delivered to thepatient, according to an embodiment of the present invention. While anydevice may be used to breach the impermeable membranes 152, a doseescalation pen or stylet 172 similar to that shown in FIGS. 26-31 may beadvantageously used. An actuator 192, such as a thumb actuated wheel,may be coupled to a pointed extendible portion 200 of the pen 172.Actuating the actuator 192 may cause the pointed and extendible portion200 to extend in length from a first length 202 shown in FIGS. 26-28, toa second length 204 shown in FIGS. 29-31. At some time afterimplantation of the pump 100, the patient may require a greater dose ofpharmaceutical agent than provided by the initial dose, which initialdose is driven by the osmotic engine 108 swelling in response to waterentering the initial water access port 132. Without removing the pump100 from the patient, the physician may, according to the presentinvention, use a dose escalation pen or stylet to increase the effusionrate of the pharmaceutical agent from the pump 100 in a simple office oroutpatient procedure.

[0080] For clarity of illustration, only the first and secondimpermeable membrane cans 114, 116 of the pump 100 are shown in FIGS.26-31. In the state illustrated in FIG. 26, the impermeable membranes152 prevent any water from the patient implant site from reaching thefirst and second semipermeable membranes 120, 124. When the physicianwishes to increase the dose of pharmaceutical agent delivered to thepatient, he or she may use the dose escalation pen 172 in aconfiguration wherein the pointed extendible portion 200 thereof isextended only to the first length 202. By inserting the portion 200through the patient's skin under fluoroscopic, ultrasonic or manual(palpation) guidance, for example, the physician may breach theimpermeable membrane 152 of the first impermeable membrane can 114, asshown at FIG. 27. Preferably, the first length 202 of the extendibleportion 200 is selected so as to breach only the impermeable membrane152 of the first can 114, and not that of the second can 116.Preferably, the outer diameter of the extendible portion 200 is slightlysmaller than the outer diameter of the cans 114, 116, to enable the doseescalation pen 172 to create a wide opening when breaching theimpermeable membranes 152. Similarly, the handle portion 206 of the pen172 should have a diameter that is slightly larger than the outerdiameter of the cans 114, 116, to limit the travel of the extendibleportion 200 within the cans 114, 116. As shown in FIG. 28, once the doseescalation pen 172 is retracted after the impermeable membrane of thefirst can 114 is breached, a first water path 178 is created, from thepatient implant site through the first impermeable membrane can 114,through the first through bore 122 thereof, across the firstsemipermeable membrane 120 to the osmotic engine 108. In this state ofthe pump 100, water may now reach the osmotic engine 108 through theinitial water access port 132 and through the first impermeable membranecan 114.

[0081] Turning now to FIGS. 29-31, when the patient requires an evengreater dose of pharmaceutical agent, the physician may actuate theactuator 192 to change the length of the extendible portion 200 to thesecond length 204, which second length 204 is sufficient to penetratethe first can 114 and breach the impermeable membrane 152 of the secondimpermeable membrane can 116, as shown at 177 FIG. 31. After the doseescalation pen 172 is retracted as shown at FIG. 31, a second water path180 is created. The second water path 180 runs from the patient implantsite through the first impermeable membrane can 114, through thebreached impermeable membrane 152 of the second can 116, through thesecond through bore 126 of the second can 116, across the secondsemipermeable membrane 124 to the osmotic engine 108. In this state ofthe pump 100, water may now reach the osmotic engine 108 through theinitial water access port 132, through the first impermeable membranecan 114 as well as through the second impermeable membrane can 116.

[0082] The tube-shaped compartment 110 of the pump 100 may be pre-loadedwith one or more pharmaceutical agents 30. For example, thepharmaceutical agent may be therapeutically effective for one or more ofthe following therapies: pain therapy, hormone therapy, gene therapy,angiogenic therapy, anti-tumor therapy, chemotherapy, allergy therapy,hypertension therapy, antibiotic therapy, bronchodilation therapy,asthmatic therapy, arrhythmia therapy, nootropic therapy, cytostatic andmetastasis inhibition therapy, migraine therapy, gastrointestinaltherapy and/or other pharmaceutical therapies.

[0083] For example, the pharmaceutical agent may include an opioid, amorphine-like agonist, a partial agonist, an agonist-antagonist and/oran alpha 2-adrenoreceptor agonist. Advantageously, the pharmaceuticalagent may include morphine, hydromorphone, levorphanol, methadone,fentanyl, sufentanil, buprenorphine, pentazocine and/or butorphanol, forexample. The pharmaceutical agent may, for example, include an analgesicagent such as Dihydrocodeine, Hydromorphone, Morphine, Diamorphine,Levorphanol, Butorphanol, Alfentanil, Pentazocine, Buprenorphine,Nefopam, Dextropropoxyphene, Flupirtine, Tramadol, Oxycodone, Metamizol,Propyphenazone, Phenazone, Nifenazone, Paracetamol, Phenylbutazone,Oxyphenbutazone, Mofebutazone, Acetyl Salicylic Acid, Diflunisal,Flurbiprofen, Ibuprofen, Diclofenac, Ketoprofen, Indomethacin, Naproxen,Meptazinol, Methadone, Pethidine, Hydrocodone, Meloxicam, Fenbufen,Mefenamic Acid, Piroxicam, Tenoxicam, Azapropazone, Codein, Bupivacaine,Ketamine, Meperidine and/or [D-Ala2,D-Leu5]enkephalin (DADL). Thepharmaceutical agent may also include analgesic that is an alpha-2adrenergetic agonist such as Clonidine, Tizadine, ST-91, Medetomidine,Dexmedetomidine and/or related alpha-2 adrenergetic agonists. Theanalgesic may also include an N-methyl-D-aspartate (NMDA) receptoragonist including Dexmethorphan, Ifenprodil,(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine(MK-801), and/or related NMDA agonists. The analgesic may also include asomatostatin analog selected including Octreotide, Sandostatin,Vapreotide, Lanreotide, and/or related Somatostatin analogs, forexample. Alternatively, the pharmaceutical agent may include anon-opioid analgesic such as Ketorolac, super oxide dismutase, baclofen,calcitonin, serotonin, vasoactive intestinal polypeptide, bombesin,omega-conopeptides, and/or related non-opioid analgesics, for example.The pharmaceutical agent in the compartment 310 may be dissolved in anaqueous solution.

[0084] For pain therapy, a preferred pharmaceutical agent is Sufentanil.In that case wherein the pharmaceutical agent is (or includes)Sufentanil that is dissolved in an aqueous medium, it has been foundthat the solubility of the Sufentanil within the aqueous solutionincreases with increasing acidity of the medium. For example, the pumpsaccording to the present invention may be configured to deliverSufentanil at up to about 1500 μg/day, at a concentration of up to about500,000 μg/ml, when the Sufentanil is dissolved in an acidic aqueousmedium.

EXAMPLE

[0085] A pump according to the present invention may include apharmaceutical agent compartment 310 having a volume of 500 μl(microliters). A compartment 310 of this volume may contain 500 μl ofpharmaceutical agent solution, the solution including 250,000 μg ofSufentanil dissolved in an acidic aqueous medium. Therefore, about 1500μg/day of such pharmaceutical agent solution may be delivered to thepatient over a treatment period spanning about 167 days. Implanted intoa patient, such a pump would deliver about 3 μl of pharmaceutical agentsolution to the patient per day, each such 3 μl of pharmaceutical agentsolution containing about 1500 μl of Sufentanil.

[0086] The pharmaceutical agent may also include an anti-allergic agentincluding Pheniramine, Dimethindene, Terfenadine, Astemizole,Tritoqualine, Loratadine, Doxylamine, Mequitazine, Dexchlorpheniramine,Triprolidine and/or Oxatomide, for example. The pharmaceutical agent mayinclude one or more anti-hypertensive agents, such as Clonidine,Moxonidine, Methyldopa, Doxazosin, Prazosin, Urapidil, Terazosin,Minoxidil, Dihydralalzin, Deserpidine, Acebutalol, Alprenolol, Atenolol,Metoprolol, Bupranolol, Penbutolol, Propranolol, Esmolol, Bisoprolol,Ciliprolol, Sotalol, Metipranolol, Nadolol, Oxprenolol, Nifedipine,Nicardipine, Verapamil, Diltiazim, Felodipine, Nimodipine, Flunarizine,Quinapril, Lisinopril, Captopril, Ramipril, Fosinoprol and/or Enalapril,for example. Alternatively, the pharmaceutical agent may include anantibiotic agent such as Democlocycline, Doxycycline, Lymecycline,Minocycline, Oxytetracycline, Tetracycline, Sulfametopyrazine,Ofloaxcin, Ciproflaxacin, Aerosoxacin, Amoxycillin, Ampicillin,Becampicillin, Piperacillin, Pivampicillin, Cloxacillin, Penicillin V,Flucloxacillin, Erythromycin, Metronidazole, Clindamycin, Trimethoprim,Neomycin, Cefaclor, Cefadroxil, Cefixime, Cefpodoxime, Cefuroxine,Cephalexin and/or Cefradine, for example. Bronchodialotors andanti-asthmatic agents may also be pre-loaded into the tube-shapedcompartment 110, including Pirbuterol, Orciprenaline, Terbutaline,Fenoterol, Clenbuterol, Salbutamol, Procaterol, Theophylline,Cholintheophyllinate, Theophylline-ethylenediamine and/or Ketofen, forexample. Anti-arrhythmic agents may also be pre-loaded into the pump100, including Viquidil, Procainamide, Mexiletine, Tocainide,Propafenone and/or Ipratropium, for example. The pharmaceutical agentmay alternatively include a centrally acting substance such asAmantadine, Levodopa, Biperiden, Benzotropine, Bromocriptine,Procyclidine, Moclobemide, Tranylcypromine, Tranylpromide, Clomipramine,Maprotiline, Doxepin, Opipramol, Amitriptyline, Desipramine, Imipramine,Fluroxamin, Fluoxetin, Paroxetine, Trazodone, Viloxazine, Fluphenazine,Perphenazine, Promethazine, Thioridazine, Triflupromazine, Prothipendyl,thiothixene, Chlorprothixene, Haloperidol, Pipamperone, Pimozide,Sulpiride, Fenethylline, Methylphenildate, Trifluoperazine, Oxazepam,Lorazepam, Bromoazepam, Alprazolam, Diazepam, Clobazam, Buspirone and/orPiracetam, for example. Cytostatics and metastasis inhibitors may alsobe pre-loaded within the pump 100 of the present invention, includingMelfalan, Cyclophosphamide, Trofosfamide, Chlorambucil, Busulfan,Prednimustine, Fluororacil, Methotrexate, Mercaptopurine, Thioguanin,Hydroxycarbamide, Altretamine and/or Procarbazine, for example. Otherpharmaceutical agents that may be pre-loaded include anti-migrane agentssuch as Lisuride, Methysergide, Dihydroergotamine, Ergotamine and/orPizotifen or gastrointestinal agents such as Cimetidine, Famotidine,Ranitidine, Roxatidine, Pirenzipine, Omeprazole, Misoprostol,Proglumide, Cisapride, Bromopride and/or Metoclopramide.

[0087] The present invention is also a kit, including an implantableosmotic pump 100, a catheter 102 configured to attach to the pump 100and/or dose escalation pen(s) 172 configured to breach the impermeablemembranes 152 of the first and/or second cans 114, 116.

[0088] There may be instances wherein it is desired to shut the pumpdown. For example, an adverse reaction to the pharmaceutical agent mayhave occurred. FIGS. 32 and 33 are plan and perspective views,respectively, of a membrane enclosure 112, according to embodiment ofthe present invention that addresses this need. As shown therein, themembrane enclosure 112 of FIGS. 32 and 33 is identical to the membraneenclosure of FIGS. 11 and 12, but for the presence of the structurereferenced at 209. Reference 209 denotes an OFF switch that isconfigured to enable the physician to nullify or substantially nullifythe osmotic pressure differential across any and all semipermeablemembranes such as shown at 120 or 124. The OFF switch 209 includes anOFF switch impermeable membrane 210 and an OFF switch impermeable lumen211. When and if the OFF switch impermeable membrane 210 is breached,fluid from the patient's implant site flows into the OFF switch lumen211, bypasses the semipermeable membranes, and flows directly to theosmotic engine 108. Thus, any existing osmotic pressure that may havedeveloped across such semipermeable membranes is reduced to zero orsubstantially zero, which correspondingly reduces the pump's drivingforce and reduces the delivery rate of the pharmaceutical agent to zeroor about zero. The pump may then be explanted from the patient at willor may simply be left in place.

[0089]FIG. 34 is an exploded view of another embodiment of an osmoticpump according to the present invention. FIG. 34 is similar to FIG. 1,but for the osmotic engine 108. Accordingly, the description of thestructures in FIG. 1 that are identical to structures in FIG. 34 isincorporated herein by reference. In FIG. 34, at least a portion of theosmotic engine is disposed within the tube 109, at or near the proximalend 184 thereof. The tube, in this case, is preferably rigid and may beformed of, for example, stainless steel or titanium. In this manner, theexpansion of the osmotic engine 108 may be entirely constrained withinthe tube 109, thereby pushing the piston 162 within the tube 109 towardthe proximal end 186 thereof.

[0090]FIG. 35 is an exploded view of a three-stage osmotic pump 300,according to another embodiment of the present invention. FIG. 36 is atop view of a three stage osmotic pump according to the presentinvention, showing the internal structure thereof in dashed lines. FIGS.37 and 38 are cross-sectional views of a three stage osmotic pumpaccording to the present invention, taken along cross-sectional line BB′and AA′ of FIG. 36. Considering now FIGS. 35-38 collectively, theconstituent elements of the pump 300 that are similar to correspondingelements in FIG. 2 are identified by the same reference numerals and thedetailed description thereof is omitted here. As shown, the osmotic pump300 includes a substantially saucer-shaped housing that includes a firsthousing half 302 and a second housing half 304 that mates with the firsthousing half 302. In contradistinction to the embodiment shown in FIG.2, the osmotic pump 300 of FIG. 35 does not include a tube, such as tube109. Instead, when mated together, the first and second halves 302, 304of the pump housing together define a tube-shaped and fluid-tightcompartment 310 that is adapted to enclose a pharmaceutical agent. Thecompartment 310 is substantially toroidal in shape, in that it resemblesa tube that curves around the osmotic engine 306, following the outercurvature of the pump housing throughout most of its length. Thetube-shaped compartment 310 defines a first end 330 that is in fluidcommunication with the osmotic engine 306 through a passageway 332 and asecond end 334 adjacent the compartment outlet 314 that is formed whenthe first and second halves 302, 304 of the housing are joined together.

[0091] The pump 300 includes a piston 316 that is configured and adaptedto travel within the compartment 310 in response to the force exertedthereon by the osmotic engine 306. As the piston 316 travels within thecompartment 310, it displaces a volume of pharmaceutical agent. Thepiston 316, when the pump 300 is first implanted, is located adjacentthe first end 330 of the compartment 310 and thereafter travels from thefirst end 330 toward the second end 334, displacing a volume ofpharmaceutical agent as it travels. FIG. 41 shows a cross-section of anexemplary embodiment of a piston 316. As shown therein, the piston 316may define a leading end 322 and a trailing end 324. Additionally, toreduce the surface area of the piston 316 that contacts the wall of thepharmaceutical agent compartment 310, the outer surface of the pistonmay define one or more throughs 328 and ridges 326, thereby furtherfacilitating the travel of the piston 316 through the compartment 310.

[0092] Returning now to FIG. 35, the pump 300, when configured forsystemic delivery of a pharmaceutical agent (as is the case wherein thepump is implanted subcutaneously, for example), may include a filterassembly 312. The filter assembly 312 is configured to fit within thecompartment outlet 314, so as to maintain the substantially circularfootprint of the pump 300, as shown most clearly in FIG. 36. Thestructure of the filter assembly 312 is further described below, withreference to FIGS. 39 and 40. Functionally, the filter assembly 312filters the flow of the pharmaceutical agent from the pump 300 to theimplant site within the patient or to the aqueous environment in whichthe pump is deployed. The filter assembly 312 prevents the passage ofcrystallized pharmaceutical agents to the patient. Crystallizedpharmaceutical agents present a danger to the patient, in that thecrystallized portion may contain an excess amount of agent and may causean overdose.

[0093] Assuming that the tube-shaped compartment 310 is substantiallycircular in cross-section, the volume of pharmaceutical agent that maybe contained therein may be estimated by:

n/360[¼ Π²(a+b)(b−a)²

[0094] where, as shown in FIG. 36b (which figure is not shown to thesame scale as FIG. 36a), a is the inner radius of the compartment 310, bis the outer radius of the compartment 310 and n represents the numberof degrees that the compartment 310 is coiled around the pump 300, asshown by arrow 350. As shown in the embodiment illustrated in FIG. 36b,n is about 270°, as the portion of the compartment 310 that is free toenclose pharmaceutical agent (i.e., from the leading edge 317 of thepiston 316 to the proximal edge 313 of the filter assembly 312) spansabout ¾ of the circumference of the pump 300.

[0095] The pump 300 may also include a ring 308. The ring 308 ispreferably formed of the same material as the first and second housinghalves 302, 304 such as stainless steel, titanium or alloys thereof, forexample. To assemble the pump 300, the piston 316 may be placed adjacentthe first end 330 of the compartment 310 and the osmotic engine 306 maybe centered between the first and second housing halves 302, 304. Thefirst and second housing halves 302, 304 may then be welded together,along the circumferential seam thereof. The first and second impermeablemembrane cans 114, 116 may then be inserted into the membrane enclosure,properly aligned therein and secured thereto. The ring 308 may then beinserted into the central opening formed by the first and second housinghalves 302, 304 and the semipermeable membrane enclosure 112, completewith the first and second impermeable cans 114, 116 may then be droppedinto the central opening of the ring 308, taking care to align the firstthrough bore 124 with the first semipermeable membrane well 146 and thesecond through bore 124 with the second semipermeable membrane well 148.The enclosure 112 may then be welded to the ring 308 and the ring 308may be welded to the first half 302 of the pump housing (not necessarilyin that order). The compartment 310 may then be filled withpharmaceutical agent (not shown in FIG. 35) and the filter assembly 312may thereafter be fitted within the compartment outlet 314 and securedtherein. Note that the initial dose semipermeable membrane fitted withinthe initial dose semipermeable membrane well 336 is not shown in FIGS.35-38, nor is the first semipermeable membrane fitted within the firstsemipermeable membrane well 146 or the second semipermeable membranefitted within the second semipermeable membrane well 148. The membraneenclosure 112 may also incorporate the OFF switch features shown inFIGS. 32 and 33. According to the embodiment of the present inventionshown in FIGS. 35-38, the pump 300 is adapted to deliver apharmaceutical agent or agents at three distinct rates. The first orinitial rate occurs when the pump 300 is implanted within the patientand only the initial water access port 130 is in fluid communicationwith the fluid environment of the pump's implant site within thepatient. In this configuration, water from the implant site enters thepump at 130, crosses the initial dose semipermeable membrane in thesemipermeable membrane well 336 and comes into contact with the osmoticengine 306, causing the engine 306 to swell and to push the piston 316toward the second end 334 of the compartment 310 at an initial firstrate. Thereafter, the physician may puncture the impermeable membrane ofthe first can 114, thereby causing water form the implant site to entertherein, cross the first semipermeable membrane within the firstsemipermeable membrane well 146 and reach the osmotic engine 306. Thedelivery rate of the pump 300 is now increased from its first, initialrate to a second, larger rate, as more water from the patient implantsite is reaching the osmotic engine 306, causing it to swell at a fasterrate, thereby causing to piston 316 to travels within the compartment310 at a corresponding second, faster rate. When the second impermeablemembrane can 116 is breached, water from the implant site enterstherein, crosses the second semipermeable membrane within the secondsemipermeable membrane well 148 and reaches the osmotic engine 306. Thedelivery rate of the pump 300 is now increased from its second rate to athird, even greater rate, as more water from the patient implant sitereaches the osmotic engine 306, causing it to swell at a faster rate,thereby causing to piston 316 to travel within the compartment 310 at athird, faster rate, thus displacing a greater amount of pharmaceuticalagent than either the initial or second rates.

[0096]FIG. 39 is a cross-sectional view of the filter assembly 312 ofFIG. 35 and FIG. 40 is a front view of the filter assembly 312 of FIG.35. As shown in FIGS. 35 and 39-40, the filter assembly 312 may be (butneed not be) shaped as a slanted and truncated circular cylinder. Thefilter assembly 312 defines a proximal end 313 and a distal end 315. Theassembly 312 further defines a pharmaceutical agent inlet 321 thatemerges at the proximal end 313 and a pharmaceutical agent outlet 320that emerges at the distal end of the filter assembly 312. Between theinlet 321 and the outlet 320, the filter assembly includes a filter 318.According to the present invention, the filter 318 may include a plug ofporous material that defines a plurality of pores. The pores, accordingto an embodiment of the present invention, may range from about 2microns in average pore size to about 80 microns in average pore size,for example. For example, the average pore size of the porous materialof the filter 318 may be selected within the range of about 5 microns toabout 20 microns.

[0097] The porous material of the filter 318 may be selected to behydrophilic or hydrophobic, depending upon, for example, the nature ofthe pharmaceutical agent contained in the pump 300. The pharmaceuticalagent in the compartment 310 may be dissolved in an aqueous solution.Alternatively, the pharmaceutical agent in the compartment 310 of thepump 300 may be dissolved in a non-aqueous solution, such as alcohol(benzyl alcohol, for example). In such a case, the filter assembly 318may include a filter that is substantially hydrophobic in nature, whichwould allow the passage of a hydrophobic solution, but would not admitthe passage of a (or a substantial amount of a hydrophilic solution suchas water. Water (or substantial amounts thereof) from the patientimplant site, therefore, could not get into the pump 300 and only thepharmaceutical agent could get out, into the patient. Alternatively, theporous material 318 may have hydrophilic characteristics. When theporous material 318 of the filter assembly 312 is hydrophilic, relianceis made on the pressure differential across the porous material 318(higher on the proximal end 313 than on the distal end 315 end thereof,due to the pressure exerted by the osmotic engine 306) as well as on thepore size of the porous material 318 to limit the diffusion into thepump 300. The pore size may be selected depending upon the magnitude ofthe pressure differential across the filter assembly 312, the length ofthe filter 318, the nature of the pharmaceutical agent to be delivered(for example, some pharmaceutical agent including large-sized proteinmolecules such contained in many pain medications may require a filter318 defining relatively large size pores) and the aspect ratio of thefilter 318 (ratio of aggregate pore size to length of filter 318), amongother factors. Suitable materials for the porous material of the filter318 may be obtained from, for example Millipore Corp.(http://www.millipore.com), Porex Corp. (http//:www.porex.com) andothers.

[0098]FIGS. 42, 43 and 44 show a perspective view, an exploded view anda top view of a single stage osmotic pump according to anotherembodiment of the present invention, with the top view of FIG. 44showing internal components thereof in dashed lines. The pump 400includes first and second housing halves 302, 304, filter assembly 312,piston 316, osmotic engine 306 and ring 308, each of which being similaror identical to those structures in FIGS. 35-38 referenced by the samenumerals. A detailed description of these structures is, therefore,omitted here. The single-stage pump 400 may include a semipermeablemembrane enclosure 412. The semipermeable membrane enclosure 412 maydefine a water access port 430 through which water from the patientimplant site enters the pump 400. The enclosure 412 also defines a wateroutlet port 438, thorough which water comes into contact with theosmotic engine 306. Between the water inlet port 430 and the wateroutlet port 438 is disposed a semipermeable membrane. The water inletport 430 may be covered by an impermeable membrane of stainless steel ortitanium, for example. Moreover, a saturated saline solution may bepresent between the impermeable membrane covering the water inlet port430 and the semipermeable membrane within the enclosure 412. Such asaturated saline solution maintains the semipermeable membrane in ahydrated state, and speeds up the initial delivery of the pharmaceuticalagent contained in the compartment 310 of the pump 400 once the(optional) impermeable membrane covering the water inlet port 430 isbreached. Such an impermeable membrane would be included in the pump 400only if it was desired to implant the pump 400 in an inactive state and,at some later time, activate it so as to initiate the delivery of thepharmaceutical agent contained therein. The single stage pump 400 mayalso include the OFF switch features shown in FIGS. 32 and 33.

[0099] The pharmaceutical agent compartment of the pumps according tothe present invention, as noted above, may contain sufentanil, forexample, and may also contain other medications. Depending upon theclinical indication, the pumps according to the present invention may beconfigured for intravascular, subcutaneous, epidural, intrathecal orintraventricular use. Table 1 below details exemplary maximum expecteddosages of Sufentanil for above-listed uses. TABLE 1 Expected MaximumDosage of Sufentanil (μg/day) Intravascular 1500 Subcutaneous 1500Epidural 500 Intrathecal 50 Intraventricular 25

[0100] Table 2 below shows exemplary delivery schedules for pumpsaccording to the present invention having a diameter of 1.8 cm and acompartment 310 having a capacity of 200 mg, a diameter of 2.8 cm and acompartment 310 having a capacity of 500 mg and a diameter of 5.0 cm anda compartment 310 having a capacity of 2000 mg over selected deliveryrates (in mg/day) ranging from 0.50 mg/day to 20.0 mg/day. ExemplaryDelivery Schedule Months of Delivery 1.8 cm diameter 2.8 cm diameter 5.0cm diameter Delivery Rate 200 mg capacity 500 mg capacity 2000 mgcapacity (mg/day) (Without dose escalation) (With dose escalation) (Withdose escalation) 0.50 12 — — 0.75 8 12 — 2.00 3.3 6 — 5.00 — 3.3 12 10.0— — 6 20.0 — — 3.3

[0101] The present invention may be implanted under the patient's skinin an outpatient setting. The implantation procedure may be performedwith a local anesthetic and may be carried out in as little as 15-20minutes, for example. Depending upon the implant site, a small 0.5 to0.75 inch incision may be all that is required, which incision may laterbe closed with one or more STERI-STRIP® skin closure devices or sutures,for example. The thin, circular shape of the pumps according to thepresent invention facilitates placement thereof in a number of locationsthroughout the patient's body, including the chest wall, the lower back,the arms and legs, the neck and even under the scalp, to identify a fewexemplary locations. It is to be understood, however, that the abovelist of possible implant sites is not to be construed as limiting thelocations at which the present pumps may be implanted, as those of skillin this art may recognize. The present invention has been presentedwithin the context of pain management and of drugs of a potencycomparable to Sufentanil. However, the present invention may be scaledappropriately to deliver any volume of drug at any potency level.

[0102] While the foregoing detailed description has described preferredembodiments of the present invention, it is to be understood that theabove description is illustrative only and not limiting of the disclosedinvention. Those of skill in this art will recognize other alternativeembodiments and all such embodiments are deemed to fall within the scopeof the present invention. Thus, the present invention should be limitedonly by the claims as set forth below.

What is claimed is:
 1. An implantable osmotic pump for delivering apharmaceutical agent to a patient, comprising: a catheter; an osmoticengine; a pharmaceutical agent compartment; a volume of pharmaceuticalagent that includes Sufentanil within the pharmaceutical agentcompartment, and a piston disposed within the compartment, thecompartment being configured such that the osmotic engine causes thepiston to travel within the compartment along an arcuate path anddeliver the pharmaceutical agent through the catheter when the pump isimplanted in the patient, wherein the pump is configured for: a dailydelivery rate of Sufentanil of up to about 125 micrograms per day whenthe catheter is placed intraventricularly; a daily delivery rate ofSufentanil of up to about 250 micrograms per day when the catheter isplaced intrathecally; a daily delivery rate of Sufentanil of up to about750 micrograms per day when the catheter is placed epidurally; a dailydelivery rate of Sufentanil of up to about 1500 micrograms per day whenthe catheter is placed subcutaneously, and a daily delivery rate ofSufentanil of up to about 1500 micrograms per day when the catheter isplaced intravascularly.
 2. The pump of claim 1, wherein the compartmentis disposed at least partially around the osmotic engine.
 3. The pump ofclaim 1, wherein the osmotic engine includes a base, a cylindrical wallattached to the base and a free end opposite the base.
 4. The pump ofclaim 1, further including a housing configured to enclose at least theosmotic engine and the compartment.
 5. The pump of claim 4, wherein thehousing includes a first housing half and a second housing half thatmates with the first housing half.
 6. The pump of claim 5, wherein eachof the first and second housing halves define a saucer shape.
 7. Thepump of claim 5, wherein each of the first and the second housing halvesare substantially circular in shape.
 8. The pump of claim 5, wherein thefirst housing half defines a substantially circular opening.
 9. The pumpof claim 1, further including a membrane enclosure, the membraneenclosure being partially surrounded by the osmotic engine and includingan initial dose semipermeable membrane that is configured to allow waterfrom the patient to reach the osmotic engine when the pump is implanted.10. The pump of claim 9, wherein the pump is configured to deliver aninitial dose of the pharmaceutical agent to the patient at a selectedinitial infusion rate, the selected initial infusion rate being relatedto at least one of a thickness, a composition and a surface area of theinitial dose semipermeable membrane.
 11. The pump of claim 9, whereinthe initial dose semipermeable membrane is fitted with an initial doseimpermeable membrane that initially seals the initial dose semipermeablemembrane.
 12. The pump of claim 11, further including a volume of asaturated saline solution between the initial dose semipermeablemembrane and the initial dose semipermeable membrane.
 13. The pump ofclaim 9, further including a dose escalation assembly fitted in themembrane enclosure, the dose escalation assembly being adapted toselectively increase an amount of water from the patient that reachesthe osmotic engine when the pump is implanted.
 14. The pump of claim 13,wherein the dose escalation assembly includes a first impermeablemembrane configured to enable water from the patient to reach theosmotic engine through a first fluid path only after being breached. 15.The pump of claim 13, wherein the dose escalation assembly includes: afirst impermeable membrane configured to enable water from the patientto reach the osmotic engine through a first fluid path only after beingbreached, and a second impermeable membrane configured to enable waterfrom the patient to reach the osmotic engine through a second fluid pathonly after being breached, the first path being distinct from the secondpath.
 16. The pump of claim 15, wherein the first and second impermeablemembranes are disposed in the membrane enclosure in a stackedconfiguration wherein the first impermeable membrane must be breachedbefore the second impermeable membrane can be breached.
 17. The pump ofclaim 15, wherein the first fluid path includes a first semipermeablemembrane and wherein the second fluid path includes a secondsemipermeable membrane that is distinct from the first semipermeablemembrane.
 18. The pump of claim 17, wherein the pump is configured todeliver a first dose of the pharmaceutical agent to the patient at aselected first infusion rate and a second dose of the pharmaceuticalagent to the patient at a selected second infusion rate that is greaterthan the first infusion rate, the selected first and second infusionrates being related to at least one of a thickness, a composition and asurface area of the first and second semipermeable membranes,respectively.
 19. The pump of claim 1, wherein the osmotic engineincludes a hygroscopic salt.
 20. The pump of claim 1, wherein theosmotic engine includes an absorbent polymer.
 21. The pump of claim 20,wherein the absorbent polymer includes a material selected from a groupincluding poly(acrylic acid), potassium salt; poly(acrylic acid), sodiumsalt; poly(acrylic acid-co-acrylamide), potassium salt; poly(acrylicacid), sodium salt-graft-poly(ethylene oxide); poly (2-hydroxethylmethacrylate); poly(2-hydroxypropyl methacrylate) andpoly(isobutylene-co-maleic acid) or derivatives thereof.
 22. The pump ofclaim 1, wherein the compartment has a substantially constant innerdiameter over a length thereof.
 23. The pump of claim 1, wherein thecompartment has a non-constant inner diameter over a length thereof. 24.The pump of claim 1, wherein the catheter includes a radiopaque tip. 25.The pump of claim 1, wherein the piston includes one of a sphere, anelastomeric cylinder and an elastomeric conical section.
 26. The pump ofclaim 25, wherein the piston includes at least one of stainless steel, arefractory metal, plastic, nylon and rubber.
 27. The pump of claim 1,wherein the sufentanil is at a concentration up to about 500,000 μg/mL.28. The pump of claim 13, wherein the dose escalation assembly includes:a first saturated saline solution between the first impermeable membraneand the first semipermeable membrane, and a second saturated salinesolution between the second impermeable membrane and the secondsemipermeable membrane.
 29. A method of delivering a pharmaceuticalagent to a patient, comprising steps of: implanting a pump into thepatient, the pump including a pump engine and a compartment adapted tostore a pharmaceutical agent, and causing a piston to travel a distancewithin the compartment along an arcuate path and to deliver a dose ofpharmaceutical agent out of the compartment.
 30. The method of claim 29,wherein the implanting step is carried such that the pharmaceuticalagent is delivered one of intravascularly, subcutaneously, epidurally,intrathecally and intraventricularly.
 31. The method of claim 30,wherein the pharmaceutical agent includes Sufentanil and wherein thepump is configured for: a daily delivery rate of Sufentanil of up toabout 125 micrograms per day when the implanting step is carried outsuch that the pharmaceutical agent is delivered intraventricularly; adaily delivery rate of Sufentanil of up to about 250 micrograms per daywhen the implanting step is carried out such that the pharmaceuticalagent is delivered intrathecally; a daily delivery rate of Sufentanil ofup to about 750 micrograms per day when the implanting step is carriedout such that the pharmaceutical agent is delivered epidurally; a dailydelivery rate of Sufentanil of up to about 1500 micrograms per day whenthe implanting step is carried out such that the pharmaceutical agent isdelivered subcutaneously, and a daily delivery rate of Sufentanil of upto about 1500 micrograms per day when the implanting step is carried outsuch that the pharmaceutical agent is delivered intravascularly.
 32. Themethod of claim 30, wherein travel of the piston within the compartmentcauses a delivery of a volume up to about 20 μL/day over a treatmentperiod.
 33. The method of claim 29, further comprising the step ofselectively increasing the dose in a stepwise manner over a treatmentperiod without removing the pump from the patient.
 34. The method ofclaim 33, wherein the pump engine includes an osmotic engine and whereinthe pump includes an initial dose semipermeable membrane initiallyexposed to the patient and at least one second semipermeable membraneinitially not exposed to the patient and wherein the increasing stepincludes a step of selectively exposing the at least one secondsemipermeable membrane to the patient.
 35. The method of claim 29,wherein the pump the engine includes an osmotic engine in fluidcommunication with the piston and wherein the causing step includes astep of increasing a volume of the osmotic engine.
 36. A pump,comprising: a pump engine; a compartment adapted to store a fluid, thecompartment being disposed at least partially around the pump engine,and a piston disposed within the compartment, the compartment and theengine being configured to cause the piston to travel within thecompartment along an arcuate path and to force a volume of the fluid outof the pump.
 37. The pump of claim 36, wherein the pump engine includesan osmotic engine.
 38. The pump of claim 36, wherein the fluid includesa pharmaceutical agent.
 39. The pump of claim 36, further including acatheter coupled to the compartment.
 40. The pump of claim 36, whereinthe pump is fully implantable in a body and wherein pump engine and thecompartment are enclosed in a biocompatible pump housing.
 41. The pumpof claim 36, further including a dose escalation assembly, theescalation assembly being configured to selectively increase the dose offluid delivered.
 42. The pump of claim 36, wherein the dose escalationassembly comprises means for increasing the dose delivered in a stepwisemanner.
 43. The pump of claim 36, wherein the piston includes one of asphere, an elastomeric cylinder and an elastomeric conical section.